Heteroaromatic aldimines

Aromatic and heteroaromatic aldimines were effectively converted into vinylogous Mannich products 31 with complete y regioselectivity and with typically 80 90% ee. The reaction could easily be run in a three component fashion, starting directly from an aldehyde, para anisidine, and silyl dienolate 30 obviating the need to prepare the imine in a separate reaction. In contrast to most other protocols that required a salicyl imine moiety in the substrate for selectivity issues, here the amine component within the imine could just be a phenyl group or any para substituted phenyl group. 

Subsequent investigations led to the identification of a superior, second generation catalyst 35 that improved the enantioselectivity of the reaction for most substrates considerably. With a simple change of the para methyl group within the 3,3 mesityl groups of the BINOL backbone for a para tert butyl group, most aromatic and heteroaromatic aldimines were now converted into the products with around 90% ee and in select cases with >95% ee (Scheme 5.10) (M. Sickert and C. Schneider, unpublished results). 

Two years after the discovery of the first asymmetric Br0nsted acid-catalyzed Friedel-Crafts alkylation, the You group extended this transformation to the use of indoles as heteroaromatic nucleophiles (Scheme 11). iV-Sulfonylated aldimines 28 are activated with the help of catalytic amounts of BINOL phosphate (5)-3k (10 mol%, R = 1-naphthyl) for the reaction with unprotected indoles 29 to provide 3-indolyl amines 30 in good yields (56-94%) together with excellent enantioselec-tivities (58 to >99% ee) [21], Antilla and coworkers demonstrated that A-benzoyl-protected aldimines can be employed as electrophiles for the addition of iV-benzylated indoles with similar efficiencies [22]. Both protocols tolerate several aryl imines and a variety of substituents at the indole moiety. In addition, one example of the use of an aliphatic imine (56%, 58% ee) was presented. 

The same group expanded the scope of the aza-Diels-Alder reaction of electron-rich dienes to Brassard s diene 97 (Scheme 37) [60]. In contrast to Danishefsky s diene, it is more reactive, but less stable. Akiyama et al. found chiral BINOL phosphate (R)-3m (3 mol%, R = 9-anthryl) with 9-anthryl substituents to promote the [4 + 2] cycloaddition of A-arylated aldimines 94 and Brassard s diene 97. Subsequent treatment with benzoic acid led to the formation of piperidinones 98. Interestingly, the use of its pyridinium salt (3 mol%) resulted in a higher yield (87% instead of 72%) along with a comparable enantioselectivity (94% ee instead of 92% ee). This method furnished cycloadducts 98 derived from aromatic, heteroaromatic, a,P-unsaturated, and aliphatic precursors 94 in satisfactory yields (63-91%) and excellent enantioselectivities (92-99% ee). NMR studies revealed that Brassard s diene 97 is labile in the presence of phosphoric acid 3m (88% decomposition after 1 h), but comparatively stable in the presence of its pyridinium salt (25% decomposition after 1 h). This observation can be explained by the fact that the pyridinium salt is a weak Brpnsted acid compared to BINOL phosphate 3m. 

Chemistry of heteroaromatic hydroxy-, mercapto-, and selenolo-aldimines 92KGS5. 

Activated organic electrophiles such as chloro-, fluoro-, or methoxybenz-aldimines [91], various nitrogen-heteroaromatic chlorides [92], and chloroenynes... 

Akiyama and coworkers, who had pioneered BINOL-derived phosphoric acids, noticed that aldimines 365 available from 2-aminophenol and aromatic, heteroaromatic, and cinnamyl aldehydes can be activated by the chiral acid catalyst 367, so that they are electrophilic enough to react with silyl ketene acetals 366 in diastereoselective and enantioselective Mannich reactions. Thus, P-amino esters 368 are formed with a high preference for the syn-diastereomers that are obtained in high enantiomeric excess (Scheme 5.96) [182]. 

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